JPS6150978A - Pyridine derivative and preparation thereof - Google Patents

Pyridine derivative and preparation thereof

Info

Publication number
JPS6150978A
JPS6150978A JP59171069A JP17106984A JPS6150978A JP S6150978 A JPS6150978 A JP S6150978A JP 59171069 A JP59171069 A JP 59171069A JP 17106984 A JP17106984 A JP 17106984A JP S6150978 A JPS6150978 A JP S6150978A
Authority
JP
Japan
Prior art keywords
compound
formula
reaction
formulas
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
JP59171069A
Other languages
Japanese (ja)
Other versions
JPH0244473B2 (en
Inventor
Akira Nohara
野原　昭
Yoshitaka Maki
牧　良孝
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=15916456&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=JPS6150978(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to JP59171069A priority Critical patent/JPS6150978A/en
Priority to US06/760,568 priority patent/US4628098A/en
Priority to AT85305458T priority patent/ATE42554T1/en
Priority to DE19975020C priority patent/DE19975020I2/en
Priority to EP19850305458 priority patent/EP0174726B1/en
Priority to DE19975017C priority patent/DE19975017I2/en
Priority to DE8585305458T priority patent/DE3569736D1/en
Priority to DK356485A priority patent/DK171340B1/en
Priority to AU45895/85A priority patent/AU570130B2/en
Priority to IE197685A priority patent/IE58363B1/en
Priority to PH32628A priority patent/PH20946A/en
Priority to GR851981A priority patent/GR851981B/el
Priority to ZA856117A priority patent/ZA856117B/en
Priority to ES546152A priority patent/ES8607288A1/en
Priority to KR1019850005863A priority patent/KR920002128B1/en
Priority to UA3947161A priority patent/UA7140A1/en
Priority to CA000488662A priority patent/CA1255314A/en
Priority to SU3947161A priority patent/SU1507211A3/en
Priority to NO853226A priority patent/NO163131C/en
Priority to HU853151A priority patent/HU195210B/en
Publication of JPS6150978A publication Critical patent/JPS6150978A/en
Priority to US06/937,193 priority patent/US4689333A/en
Priority to MYPI87002685A priority patent/MY102116A/en
Publication of JPH0244473B2 publication Critical patent/JPH0244473B2/ja
Priority to SG1032/91A priority patent/SG103291G/en
Priority to HK47/92A priority patent/HK4792A/en
Priority to MX9203043A priority patent/MX9203043A/en
Priority to LV920583A priority patent/LV5091A3/en
Priority to GEAP1993601A priority patent/GEP19960313B/en
Priority to LTRP440A priority patent/LT2118B/en
Priority to NL930109C priority patent/NL930109I2/en
Priority to BG98459A priority patent/BG60415B2/en
Priority to NO1995002C priority patent/NO1995002I1/en
Priority to LV960208A priority patent/LV5775B4/en
Granted legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

NEW MATERIAL:A pyridine derivative expressed by formula I (R<1> is H, methoxy or trifluoromethyl; R<2> and R<3> are H or methyl; R<4> is 2-5C fluorinated lower alkyl; n is 0 or 1) or a salt thereof. EXAMPLE:2-[3-Methyl-4-(2,2,3,3,3-pentafluoropropoxy )pyridin-2-yl]methylthioimidazole. USE:Useful as an antiulcer agent, having improved inhibitory action on gastric acid secretion, protective action on gastric mucosa and antiulcer action and stability of physical properties with low toxicity, and useful as a preventing and treating agent for gastric ulcer, duodenal, ulcer, gastritis, etc. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III (X is halogen) in the presence of a base preferably at 20-80 deg.C to give the compound expressed by formula I (n is 0). The amount of the base to be used for the reaction is preferably within 2-4 equivalent range.

Description

【発明の詳細な説明】 ｊｉ２業上の利用分野 本発明は、抗潰瘍剤などとして有月なピリジン誘導体お
よびその辺迫法に関する。DETAILED DESCRIPTION OF THE INVENTION FIELD OF THE INVENTION The present invention relates to pyridine derivatives useful as anti-ulcer agents and related methods thereof.

従来の技術 抗潰瘍作用を有するピリジン誘導体としては、たとえば
すシ叩昭５４−１４１７８３号公報、特開ｉｊ召５Ｂ−
１３５８８１号公報などに記；；戊された化合物が知ら
れている。Prior Art Pyridine derivatives having anti-ulcer effects include, for example, Sushi Tako No. 54-141783 and Japanese Patent Application Laid-open No. ij Sho 5B-
135881 and other publications are known.

しかしながら、これらの公知化合物は【俊分泌抑制作用
を有するが、胃粘暎防禦作用は弱く、抗潰瘍剤としては
必ずしも満足すべきものとは言い難い。さらには、不安
定で分解しやすいという物性上のべ点も認められる。However, although these known compounds have a secretion-inhibiting effect, their anti-gastric mucus-preventing effect is weak, and it cannot be said that they are necessarily satisfactory as anti-ulcer agents. Furthermore, it is recognized that it is unstable and easily decomposed, which is a disadvantage in its physical properties.

発明が解決しようとする問題点 消化器潰瘍は′ＦＡ酸、ベブンン等の攻撃因子と粘液分
泌、粘ｊ畠血流等粘ｊ決側の防禦因子間のパヲンスの乱
れによシ生じるものと考えられている。従って攻９囚子
でちる胃酸分泌を抑制する作用と同時に胃粘膜の防票能
を増強する作用を併有する薬剤が求められていた。Problems to be Solved by the Invention Gastrointestinal ulcers are thought to be caused by a disturbance in the balance between attacking factors such as FA acids and chemicals and protective factors such as mucus secretion and blood flow. It is being Therefore, there has been a need for a drug that has both the effect of suppressing gastric acid secretion and the effect of enhancing the secretion ability of the gastric mucosa.

問題点を解決するだめの手段 本発明者らは、優れた胃酸分泌抑制作用、胃粘膀防別作
用、抗り７瘍作月などｔ有する抗潰瘍剤を得る目的で鋭
意研究したところ、ある種のピリジン誘導体が該目的に
合致することを見い出し、さらに研究した結果、本発明
を完成した。Means to Solve the Problems The present inventors conducted extensive research with the aim of obtaining an anti-ulcer agent that has excellent effects on suppressing gastric acid secretion, preventing gastric mucus and bladder, and has anti-ulcer properties. It was discovered that certain pyridine derivatives met the above objective, and as a result of further research, the present invention was completed.

本発明は、（１）一般式 〔式中、Ｒ１は水毒、メトキシまたはトリフルオロメチ
Ｉｖを、Ｒ２およびＲ３は同一または異なって水素また
はメチルを　Ｒ４は炭素数２ないし５のフッ素化された
低級アルキルを、ｎはｏ−ｉたは１をそれぞれ示す。〕
で表わされるピリジン誘導体またはその塩。The present invention is based on (1) a general formula [wherein R1 is hydrotoxic, methoxy or trifluoromethyl IV, R2 and R3 are the same or different and hydrogen or methyl, and R4 is a fluorinated compound having 2 to 5 carbon atoms] n represents lower alkyl, and n represents o-i or 1, respectively. ]
A pyridine derivative or a salt thereof.

（２）一般式 Ｃ式中、Ｒ１は水素、メトキＶ−ｉたけトリフルオロメ
チル云示寸。〕でπミわされる化合物と一般式〔式中、
Ｒ２およびＲ３は同一または具なって水：Ｚまたはメチ
ルを、Ｒ４はｖ２紮破２ないし５のフッ素化された俄壮
７μキルを、又はハロゲン原子をそれぞれ示す。〕で表
わされる化合物とを反応上記式中、Ｒ４で表わセれるｐ
ＡＺ’に２ないし５のフッ素化された低Ｌｌ　７　／Ｖ
キμとしては、たとえば２，２．２−）リフロロエチル
、２．２．３゜３．３−ペンタフロロプロピμ、２，２
，３．３−テトヲフワロプロピｙ、１．１．１−トリフ
ロロメチ／ｖ−２，２，２−）リフロロエチル、２゜２
．３．３，４．４．４−へブタフロロブチｐ。(2) In the general formula C, R1 is hydrogen, methoxyV-i is trifluoromethyl. ] and the general formula [wherein,
R2 and R3 are the same or consist of water: Z or methyl, and R4 represents a fluorinated compound of v2 ligation 2 to 5, or a halogen atom, respectively. ] In the above formula, p represented by R4 is
2 to 5 fluorinated low Ll 7 /V at AZ'
Examples of Kiμ include 2,2.2-)lifluoroethyl, 2.2.3°3.3-pentafluoropropyμ, 2,2
, 3.3-tetofluoropropyl, 1.1.1-trifluoromethyl/v-2,2,2-)lifluoroethyl, 2゜2
．． 3.3,4.4.4-hebutafluorobutyp.

２．２，３，３，４．４，５．５−オクタフロロベンチ
ｉｖｈどが７さげられる。2.2, 3, 3, 4.4, 5.5-octafluorobenchi ivh etc.7 are listed.

Ｘで示これるハロゲン原子としては、たとえば５位が好
ましい。The halogen atom represented by X is preferably at the 5-position, for example.

本発明の目的化合物であるサルファイドＬ１８体ＣＩ）
Ｃｎ−０）はＪＲ料料金合物Ｉｆ）と＜ｍ＞とを反応さ
せることによシ製造することが出來る。Sulfide L18 body CI) which is the object compound of the present invention
Cn-0) can be produced by reacting JR fee compound If) with <m>.

本反応は、塩基の存在下に行なうと好都合でちる。This reaction is conveniently carried out in the presence of a base.

該塩基としては、たとえば本葉化ナトリウム、水素化カ
リウムのような水緊化アμカリ金属、金Ａ％ナトリウム
のようなアルカリ金属、ナトリウムメトキシド、ナトリ
ウムエトキシドのようなナトリフムアｐ；フートや、炭
酸カリウム、宍酸ナトリウムのよりなアルカリ金属の炭
酸塩、トリエチルアミンのような有機アミン類Ｑが挙げ
られる。また反応に用いられる溶媒としては、たとえば
メタノール、エタノールのようなアルコ−μ頬やジメチ
、Ｖホルムアミド等があげられる。上巳反応に用いられ
る塩基の量は、通′盾当示よシややコ３剰量であるが、
大過剰の塩基を用いてもよい。すなわち、約２ないし１
０当量、さらに好ましくは約２ないし４当県である。上
記反応ｉ正反は、白′沿約０℃ないし用いた＋ｂ’ｊ￥
の！ん点付近までであυ、さらに好ましくは、約２０℃
ないし８０℃である。反応時間は、約０２ないし２４時
間、さらに好ましくは約０５ないし２時間でちる。The base includes, for example, aqueous alkali metals such as sodium chloride and potassium hydride, alkali metals such as sodium gold, sodium methoxide and sodium ethoxide; , alkali metal carbonates such as potassium carbonate and sodium chloride, and organic amines Q such as triethylamine. Examples of the solvent used in the reaction include alcohols such as methanol and ethanol, dimethic acid, and V-formamide. The amount of base used in the Kamishi reaction is, as is generally known, approximately 30% and 30%.
A large excess of base may be used. i.e. about 2 to 1
0 equivalents, more preferably about 2 to 4 equivalents. The above reaction i positive reaction temperature is from about 0℃ to +b'j￥
of! up to near the point υ, more preferably about 20°C
to 80°C. The reaction time is about 0.2 to 24 hours, more preferably about 0.5 to 2 hours.

また本発明の目的化合物で心るｙ−ｉｖフイニ〜誘導体
（Ｉ）（ｎ−１ンは、化合物（Ｉ）（ｎ−Ｑ）を１で化
反応に付すことによシ壱造出来る。ここで用いられる酸
化剤としては、たとえばメタクロロ；ｚｌ）安息香へン
、過自ド酸、トリフロロろ自叶俊、過マレイン「αのよ
うな１θ酸あるいは、亜臭紫酸ナトリウム、次ＪＵ”４
素ｒ設ナトリウム等が挙げられる。反応に用いられる温
媒としては、クロロホｐム、ジクロルメタン部のハロゲ
ン化炭化水素、テトフヒド口フラン、ジオキサンのよう
なエーテｔｔｚｅｔ　＋　’）メチ／ｌ’不ルムアミド
等の７ミドカ１．あるいは水等からげられ、’）’独ま
たは混合して用いることが出来るつ；゛司歌化剤の使用
量は、化合物（Ｉ）（ｎ＝０）に対してほぼ当ｒＣない
しはややスろ態量が好適でちる。すなわち、約１ないし
３当量、さらに好ましくけ約１ないし１．５昌爪である
。反応温度は水冷下から用いた溶媒のる点は近まで、通
常、水冷下から室温下で、さらに好ましくは約０℃ない
し１０℃で行なわれる。反応時［ｄｌは、厄當杓０．１
ないし２４時間、さらに好ましくは約０１ないし氷時間
である。Further, the target compound of the present invention, the y-iv derivative (I) (n-1), can be prepared by subjecting the compound (I) (n-Q) to a reaction with 1. The oxidizing agents used include, for example, metachloro;
Examples include sodium chloride. The heating medium used in the reaction includes chloroform, halogenated hydrocarbons such as dichloromethane, ethers such as tetrofuran, dioxane, etc. Alternatively, it can be extracted from water, etc., and used alone or in combination. The quantity is suitable. That is, about 1 to 3 equivalents, more preferably about 1 to 1.5 equivalents. The reaction temperature ranges from water cooling to a temperature close to the temperature of the solvent used, usually from water cooling to room temperature, more preferably from about 0°C to 10°C. At the time of reaction [dl is 0.1
01 to 24 hours, more preferably about 0.01 to 24 hours, more preferably about 0.01 to 24 hours.

上記の反応によシ生成した目的化合物（Ｉ）は、再結晶
、クロマトグラフィー等の慣用の手段により単鍾、請製
することができる。The target compound (I) produced by the above reaction can be produced in a single batch by conventional means such as recrystallization and chromatography.

本発明の化合物（Ｉ）は、通常用いられる手段によシ薬
理♀的に許７Ｉされ得る塩にしてもよい。Compound (I) of the present invention may be converted into a pharmacologically acceptable salt by conventional means.

該塩としては、たとえば珊酸塊、臭素１’ｌ；ｔ　、沃
素酸塩、リンｑ塩、硝酸塩、硫酸塩、酢口が猛、クエン
酸塩などが挙げられる。Examples of such salts include silicic acid block, bromine 1'l;t, iodate, phosphorus q salt, nitrate, sulfate, suzuguchigatake, citrate, and the like.

化合物ＣＩ）において、ｎ−０でちる化合物の塩は安定
であυ、ｎ−ヱである化合物の塩は、水溶液として不安
定ではあるが存在し得る。In the compound CI), the salt of the compound represented by n-0 is stable, and the salt of the compound represented by n-e is unstable as an aqueous solution, but may exist.

次に、原料化合物（ＴＩ）の製法について３明する。Next, the method for producing the raw material compound (TI) will be explained in detail.

製法１） （１ｙ）　　　　　　　　　（ＶＩ）　　　　　　　（
■）一般式（ｒＶ）で示されるニトロ化合・１．η〔式
中Ｒ２ｐ、３　は前記と同、ＸＬ衰ｆ、表わす〕にｊ、
伏ｊｉの存在下、７　／Ｌ／）−ｉｖ６！ｉｉ；’／Ｒ
Ｆ−Ｒ４０）１　　（Ｖ　　）　　Ｃ式中Ｒ４１，−１
前記と同意凝をミにわず〕を反応させることにより、−
！貨式（■）〔式中、Ｒ２，Ｒ３，Ｒ’：・よ前記と同
意薮７ｃ表わす〕のアμコキシｒ２還ｉ’５体を１３る
ことかできろ。反応に用いられるノ共基としては、たと
えばリチウム、ナトリウム、カリウムのようなアルカリ
くたシ、１．水：ニ化ナトリウム、水素化カリウムのよ
うな水添化アルカリ４１ｔＱ　＋　ｔ−ブトキシｊ７で
プロポキンナトリウムのよりなアルフラートや炭酸カリ
ウム、炭酸リチウム９炭酸ナトリウム、炭設水索カリウ
ム、炭酸ポロナトリウムのようなアルカリ金属の炭酸あ
るいは炭酸水岩塩、カリウム、ナトリウム、リチウムの
ようなアルカリ金Ｅｉ　＋水酸化ナトリウム、水酸化カ
リウムのような水酸化アーチ／Ｌ４３’ｉ、アセトン、
メチルエチルケトンのようなケトンク１の他にアセトニ
トリμ、ジメ千ルホルムアミド、ヘキサメチルリン＾サ
トリアミド等が挙げられる。反応温度は水冷下ないし溶
ζ′ちの温点付近までの退室の温度がボばれる。反応晴
間は、約１ないし４８時間である。Manufacturing method 1) (1y) (VI) (
■) Nitro compound represented by general formula (rV)・1. η [in the formula, R2p, 3 is the same as above, representing XL decay f], j,
In the presence of Fuji, 7 /L/)-iv6! ii;'/R
F-R40)1 (V) R41,-1 in C formula
By reacting the same reaction as above, -
! Can you make 13 units of the 5 aμcoxy r2 return i' in the formula (■) [in the formula, R2, R3, R': 7c is the same as above]? Cogroups used in the reaction include, for example, alkalis such as lithium, sodium, and potassium; 1. Water: Hydrogenated alkali 41tQ + t-butoxyj7 such as sodium dilide, potassium hydride, alflate, potassium carbonate, lithium carbonate, 9 sodium carbonate, potassium chloride, pol sodium carbonate. Alkali metal carbonate or carbonate water rock salt, alkali gold Ei such as potassium, sodium, lithium + hydroxide arch/L43'i such as sodium hydroxide, potassium hydroxide, acetone,
In addition to ketones such as methyl ethyl ketone, examples include acetonitrile μ, dimethylformamide, hexamethylphosphorus^satriamide, and the like. The reaction temperature ranges from water cooling to a temperature close to the temperature of the solution ζ' when leaving the room. The reaction time is about 1 to 48 hours.

このようにして得られた化合物（ＶＩ）を無水酢酸単独
もしくは、ＦＮＣｉ’＃、過鳴累酸等の砿１そ！の存在
下に加熱（約８０ないし１２０℃）することによシ一般
式（■〕で示される２−アセトキシメチルビリジン誘ｍ
体（■）〔式中、Ｒ２，Ｒ３，Ｒ４は１）ｄｌ記と同意
義を表わす。〕が得られるう反応時１ｊ０は、通常的０
．１ないし１０時間である。Compound (VI) obtained in this manner may be mixed with acetic anhydride alone or with FNCi'#, or with a combination of fluorine and oxidized acid. By heating (approximately 80 to 120°C) in the presence of
(■) [In the formula, R2, R3, and R4 represent the same meaning as in 1) dl. ] is obtained, 1j0 is usually 0
．． 1 to 10 hours.

ついで、化合４＞Ｊ（Ｖｌｌ　）をアルカリ加水分解す
ることにより一服式（ｔｍｌンて示される２−ヒドロキ
シメグーノ１ノビリジン；誘ｒニー１．　ｔ’Ｆ−Ｃ式
中Ｒ２＋　Ｒ”　ｒ　Ｒ’　４”−１：ｉ’＋’Ｊ記と
同意義を表わす。）で聾！ムすることができる。Compound 4>J(Vll) was then subjected to alkaline hydrolysis to obtain 2-hydroxymegunoviridine, represented by tml; 4”-1: i'+' represents the same meaning as J.) is deaf! can be used.

ｉイアルカリとして（−１：、たとえば水ｊｄ化ナナト
リウム水酸化カリウム、Ａ’Ｔに！カリウム、Ｑ＜　１
′！４９ナトリウムなど７’）ｆ７’ｔ’ｘげられる。As an alkali (-1:, for example, sodium hydroxide potassium hydroxide, A'T! Potassium, Q < 1
′! 49 Sodium etc. 7') f7't'x can be obtained.

用いられるｔ７；　ｉＷとしては、たとえばメタノ−〜
、エタノール、水などが挙げられる。反応２ス度は通常
＆フ２０°ないし６０℃、反応時間は約０．１ないし２
！１聞であるうさらに化合物（−？（）を塩化チオニル
のような塩爲化剤でハロゲン化することにより一役式（
ＴＩＣ）で示される２−ハロゲノメチルビリジン誘導体
〔式中Ｒ２，１３，Ｒ４は前記と同意義を表わし、Ｘは
塩累、臭シ：］またはヨウ素ｔ−表わす。〕を製造する
ことが出光る。用いられる１容媒としてはたとえば、ク
ロロホルム、ジクロルメタン、テトラクロロエタンなど
が縫げられる。反応温度は通奮約２０°ないし８０℃で
あシ、反応時間は約０．１ないし２時間でちる。The t7 used; iW is, for example, methanol to
, ethanol, water, etc. The reaction temperature is usually 20° to 60°C, and the reaction time is about 0.1 to 2.
! Furthermore, by halogenating the compound (-?
2-halogenomethylpyridine derivatives represented by TIC) [wherein R2, 13, and R4 represent the same meanings as above, and X represents a salt, a bromine, or an iodine t-. ] It is possible to manufacture them. Examples of the medium that can be used include chloroform, dichloromethane, and tetrachloroethane. The reaction temperature is about 20° to 80°C, and the reaction time is about 0.1 to 2 hours.

製造した化合でｖ（ＩＩ）は、用いたハロゲン化剤のハ
ロゲン化水ヌ・１酸檻でちるが、これは通常直ちに化合
物（ＩＩ）との反応に用いるのが好゛ましい。In the produced compound, v(II) is treated with the halogenated water/mono-acid cage of the halogenating agent used, and it is usually preferable to use it immediately for the reaction with compound (II).

ｉＪψ法２ン （■ン　　　　　　　　　　　　　　（Ｘ）　　　　　
　　　　　　　　　　　　（ＩＴ）前記の製法１）の場
合と同様の反応にょシ一般式（■）〔式中Ｒ２゜Ｒ３は
前記と同意％ｇ　ｆｃ表わす。iJψ method 2n (■n (X)
(IT) The same reaction as in the above production method 1) is carried out using the general formula (■) [wherein R2°R3 is the same as above, expressed as %g fc.

〕の化合物を一般式（Ｘン〔式中Ｒ２，Ｒ３，Ｒ４は前
記と同意義を表わす。〕の化合物（Ｘ）に導く。] is led to a compound (X) of the general formula (X, in which R2, R3, and R4 have the same meanings as above).

ついで化合物（Ｘ）を硫酸ジメチμでメチル化して一般
式（ＸＩ　）　Ｃ式中Ｒ２，Ｒ”、　Ｒ’ハ１ｍＥト同
意義を表わす。〕とする。通常溶媒を用する必要はなく
、反応温度は約１０ｆｆ’ないし１２０ｔ：、反応時間
は約０．１ないし４時間である。Compound (X) is then methylated with dimethyl sulfate to give the general formula (XI) where R2, R'' and R' have the same meaning.Normally, there is no need to use a solvent, and the reaction The temperature is about 10 ff' to 120 t: and the reaction time is about 0.1 to 4 hours.

さらに、化合物（ＸＩ）をメタノール中で過硫酸アンモ
ニウムまたはその他の過硫酸塩のようなラジカ／Ｌ／源
と反応させることによシ前記の化合物（■）を製造する
ことができる。反応温度は約２０ないし８０℃１反応時
１ｆｒｌは約０，５ないし４時間である。Additionally, the above compound (■) can be prepared by reacting compound (XI) with a radical/L/source such as ammonium persulfate or other persulfate in methanol. The reaction temperature is about 20 to 80°C, and 1 frl per reaction is about 0.5 to 4 hours.

次に、本発明の化合物の薬理作用について述べる。Next, the pharmacological effects of the compounds of the present invention will be described.

消化品潰瘍のモデルとしては、水没拘束ストレアー債瘍
、インｒノ？シン潰１島、エタノールによる胃才占Ｉ！
！遣ｔ１１筋４５村１々のｉ！＋２瘍モデｐがらるが、
ヒトの１費夙に非常に近いモデルと考えられるものに、
佐原らのａａｓｔｒｏｅｎｔｅｒｏｌｏｇｙ、　８１巻
、７１９頁。Models for gastrointestinal ulcers include submerged restraint strain ulcers, and Inno? Sin crush 1 island, stomach fortune telling by ethanol I!
! i from 45 villages with 11 members! +2 tumor model pgaral,
What is considered to be a model that is very close to the human cost of one,
Sahara et al., Aastroenterology, vol. 81, p. 719.

１９８１年に報告されたインドメタシン四出門前庭部潰
瘍があり、実験系として有用性が高い。従って、以下に
本実験系を用いた目的化合物ＣＩ）ｍと公知化合物の代
表例とについての抗ｊ資ｊ葛作用のデータを示す。Antral ulcer caused by indomethacin was reported in 1981 and is highly useful as an experimental system. Therefore, data on the anti-reactive effects of the target compound CI)m and representative examples of known compounds using this experimental system are shown below.

突β１方法： 生後７週令のＳｐｒａｇλｅ　Ｄａｖｌｅｙ系雄注ラッ
トを２４時間絶食後宍碕に供した。被検化合物を経℃ゾ
ンデを用いて胃内に投与し、３０分後にインドメタシン
３０り／ｋｑを皮下投与した。インドメタシン投与３０
分後から１時間の間ラットにＩ′ｆｊＩ型Ｓ料（日本ク
レア、ＣＥ−２）を与え、自由に５餌させた。インドメ
タシン投与５時間後に１％エバ十二指腸とともに摘出し
、食道をクリップで閉寒した後、十二指腸から胃内に１
％ホルマリン液１０ｆｔを注入した後、十二指腸をクリ
ップで閉寒し、冑全体を１％ホμマリン液中に浸した。1 method: Seven-week-old Spragλe Davley male rats were fasted for 24 hours and then subjected to a Shishisaki test. The test compound was administered intragastrically using a C probe, and 30 minutes later, indomethacin 30 l/kq was administered subcutaneously. Indomethacin administration 30
After 1 minute, the rats were given I'fj type S food (CE-2, CLEA Japan) for 1 hour, and allowed to eat 5 meals ad libitum. 5 hours after administration of indomethacin, the duodenum was removed with 1% evaporation, the esophagus was closed with a clip, and 1% was injected into the stomach from the duodenum.
After injecting 10 ft of 1% formalin solution, the duodenum was closed with a clip, and the entire helmet was immersed in 1% formalin solution.

約１０倍）ｔ−用いて計測した。個々の動物で損傷の総
面積を測り、各群毎に面積の平均値を算出し、対照群の
値との差から抑制率を求めた。なお被検化合物およびイ
ンドメタシンはいずれも５％アラビアゴム液に３渇し、
２ｒ；ｔ／ム°ｑの容量を投与した。(approximately 10 times). The total area of damage was measured for each animal, the average value of the area was calculated for each group, and the inhibition rate was determined from the difference from the value of the control group. Both the test compound and indomethacin were dissolved in 5% gum arabic solution.
A volume of 2r;t/mu°q was administered.

実験成績： ＨＣ１ｌ、　　ＨＣ１１２ＣＦ３　　　１　　　　＜１
．ＯＨＨＨＣ１１２ＣＦ’２ＣＦ’３　　１　　　　１
．３ＥＩ　　　ＣＨ３１’ｌ　　Ｃ１１２ＣＦ２ＣＦ’
３　　１　　　　＜１．０Ｈｎ　　　ＨＣ１２ＣＦ２Ｃ
Ｆ’３　１　　　　１．３１ｉ　　　ＣＨ３Ｉ　　ｃ■
２ｃｒ２ｃｒ２ｕ　　１　　　　＜１．０章１９寺１）
ｉｉｎ百５４−１４１７８３　　実’Ｊｊｆ：ｒ　（ｆ
ｆｉｌ　２３の化合物 傘２　特開昭５８−１３５８８１　　′：Ａ施伊１３の
化合物 ａ）一群６匹のフッ）ｋ用い、いずれのイし合物も１．
３．１０および３０　ｖ：ｙＺｈｙｔ投与し、ＩＤ５０
を求めた。Experimental results: HC1l, HC112CF3 1 <1
．． OHHHC112CF'2CF'3 1 1
．． 3EI CH31'l C112CF2CF'
3 1 <1.0Hn HC12CF2C
F'3 1 1.31i CH3I c■
2cr2cr2u 1 <1.0 Chapter 19 Temples 1)
iin 1054-141783 real'Jjf:r (f
fil 23 Compound Umbrella 2 JP-A-58-135881 ':A Compound 13 a) Group of 6 animals (feed)
3.10 and 30 v:yZhyt administered, ID50
I asked for

このように、本発明化合物は公知化合物に比べて、約１
，５ないし２０倍以上優れた抗えへ多鳴イ乍用を示す。Thus, the compound of the present invention is about 1
, 5 to 20 times better resistance.

また、本発明の化合物（１）　！−１：、操れたｑ酸分
泌抑制作用、−冑粘腹防禦作月、抗后関作用を示す。Moreover, the compound (1) of the present invention! -1: Shows a controlled q-acid secretion inhibitory effect, an anti-inflammatory effect, and an anti-ejaculatory effect.

本発明の化合物（Ｉ）のｍ注については、例えば、抗潰
瘍作用の夾険に用いた化合物（Ｒ１−Ｈ。For m-injection of the compound (I) of the present invention, for example, the compound (R1-H) used for anti-ulcer activity.

Ｒ２＝ＣＢ５．　　Ｒ３−Ｈ，Ｒ’−ＣＨ２ＣＦ２ＣＦ
３．ｎ”１　　の化合物）をマウスに２ｏｏｏ　ＩＩＩ
／ｋ（ｉ経口投与しても死亡例ｔ−認めなかった。した
がって、化合物（Ｉ）は低徂性である。R2=CB5. R3-H, R'-CH2CF2CF
3. n”1 compound) to mice 2ooo III
/k(i) No deaths were observed even after oral administration. Therefore, Compound (I) has low toxicity.

このように、本発明の化合物（Ｉ）は、抗？、Ｅｔ　ｆ
′ｔｙＪ作用、胃酸分泌抑制作用、粘！］′Ａ保；屋作
用等の作用を有し、毒性は低く、しかも化学物質として
比較的安定である。したがって、本発明の化合物ＣＩ）
は、哺乳動物（例、マウス、ラット、ウサギ、犬、ネコ
、ヒトなど）の消化器潰６の治療に用いることができる
。Thus, the compound (I) of the present invention has anti-? , Et f
'tyJ action, suppressing gastric acid secretion, viscosity! ]' It has a protective effect, has low toxicity, and is relatively stable as a chemical substance. Therefore, the compounds of the invention CI)
can be used to treat gastrointestinal ulcers 6 in mammals (eg, mice, rats, rabbits, dogs, cats, humans, etc.).

本発明の化合物ＣＩ）を哺乳動物の消化器雀瘍の治療に
抗１７ｒ　Ｂ５剤として用いるには、たとえば化合物Ｃ
Ｉ）を薬理学的に許容され得る担体、賦形剤、希釈剤な
どと混合し、カブ七〃剤１錠剤、顆粒剤などの剤澗にし
て経口的に投与することができる。その投与１には、約
０．０１〜３０　Ｈ：Ｑ／に９ｌ日、さらに好ましくは
、約０．１〜３＝ｙ／ｉ；ｙ／日である。For use of the compound CI) of the present invention as an anti-17r B5 agent in the treatment of gastrointestinal ulcers in mammals, for example, compound C
I) can be mixed with pharmacologically acceptable carriers, excipients, diluents, etc., and administered orally in the form of one tablet, granules, or the like. The administration 1 is about 0.01-30 H:Q/91 days, more preferably about 0.1-3=y/i;y/day.

また、本発明の化合物ＣＩ）において、ｎ−０のｆヒ合
物は、ｎ−１の化合物ヲ製造するための原≦化合物とし
て有用である。Furthermore, in the compound CI) of the present invention, the n-0 f-hy compound is useful as a raw compound for producing the n-1 compound.

突ｊｉ、ｉ　Ｇ１ 次に、本発明方法に用論られる原イ化合物および本発明
のｒヒ合二勺（Ｉ）の製ｊコ方法を、それぞれ翠考伊１
および５・Ｊ旅回によシ具体的に説明する。Next, the raw compound used in the method of the present invention and the method for producing the compound (I) of the present invention are described in Suikoi 1, respectively.
and 5. J travel times will be explained in detail.

袷イ３０１１ ２．３−ジメチル−４−ニトロピリジン−１−オキシド
（２ｇ）を２．２，３．３−テトフフロロプロバノー／
’（１０ａｆｆ）にとかし、室温で少しずつｔ−・ブト
キシカリウム（１，６９）／Ｊえたのち、８σ〜９０℃
で２２時間加罰した。反応ｎｆ、を水でうすめ、クロロ
ホルムで抽出後代６トマグネシウムで化１珀し、ｌにｉ
ａｉ：ｉ後シリカゲルＣ７０９）のカフムにかけ、メタ
ノール−クロロホルム（１：１０）で溶出し、酢１°、
２エチルエステル−ヘキサンから再結晶すると、２．３
−ジメチ／Ｌ／−４−（２，２゜３．３−テトラ７０ロ
プロボキク〕ピリジン−１−オキシドの無色針状晶Ｚ６
ｆが得られた。融点１３８〜１３９℃ 上記と同様の方法によ）、原料化合物（ＩＶ）よシ化合
物（■）を製造した。Sokai 3011 2.3-dimethyl-4-nitropyridine-1-oxide (2 g) was dissolved in 2.2,3.3-tetoffluoroprobanol/
'(10af), and after gradually adding t-butoxypotassium (1,69)/J at room temperature, 8σ~90℃
He was punished for 22 hours. The reaction nf was diluted with water, extracted with chloroform, converted to 1 with magnesium, and added to l.
After ai:i, apply to a cuff of silica gel C709), elute with methanol-chloroform (1:10), add vinegar 1°,
Recrystallization from 2 ethyl ester-hexane yields 2.3
-Dimethy/L/-4-(2,2゜3.3-tetra70loproboxylic)pyridine-1-oxide colorless needle crystals Z6
f was obtained. Melting point: 138-139° C.), raw material compound (IV) and compound (■) were produced by the same method as above.

化合物（ＶＩ） Ｒ２Ｒ３Ｒ４Ｒ４，点（’ｅ） ！！　　　Ｈ−ＣＨ２ＣＦ２３　　１４８〜１５０ＣＨ
３ＣＨ３ＣＨ２ＣＦ３　　　１．３８〜１３９参考例２ ２．３−ジメチＡ／−４−ニトロピリジン−１−オキシ
ド（Ｌｏｆ）、メチμエチｐケトン（３ＯＮｌ）＋２．
２．３Ｎ３．３−ペンタフロロプロパノ−／’（３，０
５ａ／）、無水炭酸カリウム（３，２９ｇ）、ヘキサメ
チルリン酸トリアミド（２，０１）の混合物を７０〜８
０℃で４．５日間加熱（”二拌したのち、不溶物をろ去
し、濃縮した。残留物に水を加工、酢酸エチμエヌテル
で抽出し、硫酸マグネカラムで“ｉ：、！、、に、仁し
＋Ｈに“１′、全３．′ｆ夫し、′−°ン：’＋７恥乃
でシリカゲル（５０Ｌ＃１）のカラムにかケ、タコロホ
ｐムーメタノール（１０：１）で帛出し、ｉ＋ｊ′ｌ’
ｌ’２エナルエステルーヘキサンよりｌ’）ｉ（＋ｉ晶
すると、２　、３−！／メチル−４−（２，２，３，３
，３−ベンクフロロプロ７＋：キシ〕ピリジン−１−オ
キシドの無色針状晶２．４Ｑが得られた。「１（°ゑ点
１４８〜１４９℃上記と同（°臼の方法により、原斜化
合物（１ｖ）より化合物（■）１ＩＣ製造した。Compound (VI) R2R3R4R4, point ('e)! ! H-CH2CF23 148-150CH
3CH3CH2CF3 1.38-139 Reference Example 2 2.3-dimethyA/-4-nitropyridine-1-oxide (Lof), methyμethipketone (3ONl)+2.
2.3N3.3-pentafluoropropano-/'(3,0
5a/), anhydrous potassium carbonate (3,29g), and hexamethylphosphoric acid triamide (2,01) at 70-8
After heating at 0°C for 4.5 days (stirring twice), insoluble matter was filtered off and concentrated. The residue was treated with water, extracted with ethyl acetate, and purified with a sulfuric acid magne column. , Add 1' to the mixture + H, add all 3.'f,'-°'n:'+7 to the column of silica gel (50L #1), and add Takoroho pmu methanol (10:1). Start with i+j'l'
From l'2 enal ester-hexane, l')i (+i crystallization yields 2,3-!/methyl-4-(2,2,3,3
, 3-bencfluoropro7+:xy]pyridine-1-oxide as colorless needles 2.4Q were obtained. Compound (■) 1IC was prepared from the original diagonal compound (1v) by the same method as above at a temperature of 148-149°C.

化合物Ｕ＋＞ Ｒ２Ｒ３Ｒ４Ｈ，づ点（１） Ｃ）Ｉ３１（ＣＨ２ＣＦ’３　　　　１３１．０〜１３
１．５ＨＣｌ１３　　ＣＨ２ＣＦ’３　　　　１５３〜
１５４Ｉ（）ｌ　　Ｃ１２ＣＦ’２０Ｆ３７９〜８１＋
（Ｃ）Ｉ３　０Ｈ２ＣＦ’２ＣＦ’３　　　１４０〜１
４２ＨＨＣＨ２０Ｆ’２Ｃｒ、ｊｉ　　　７１１１状Ｈ
ＣＨ３ＣＨ２ＣＦ２ＣＦ’２Ｈ１４３，５〜１４４．５
ＣＨ３）Ｉ　　ＣＨ２ＣＦ’２ＣＦ２１１　　１３’８
〜１３９参考例３ ２．３−ジメチル−４−（２，２，３，３−テトヲ７０
ロプロボキシ）ピリジン−１−オキシド（２，６９）、
無水酢酸（８πｌ）の３面にと数、′讃（１１３）を加
え、１１０℃で４峙間かきまぜたのち、ρ樹した。歿留
物をメタノ−１ｖ（２ｏゴ）に溶かし、水酸化ナトリウ
ム（１，２ｇ）の水（５，ｔ）溶液を加え、室温で３０
分間かきまぜた。ｔ３稲後水を加え、酢酸エチルエステ
μで抽出した。硫酸マグネシウムで乾燥後、溶媒を留去
し、７リカゲ／Ｌ／（５０ｇ）のカラムＫかけ、クロロ
ホルム−メタノ−／ｌ’（１０：１）で溶呂し、イソデ
ロビルエーテμよシ再結晶すると、２−区ドロキシメチ
）ｖ−３−メチＡ／−４−（２，２，３，３−テトフフ
ロロプロポキン）ピリジンの黄色結晶１．６ｇが得られ
たう融点６７〜６８℃ 上記と同様にして以下の化合物（Ｘ７）を化合物（ＶＩ
）よシ製造した。Compound U+> R2R3R4H, points (1) C) I31 (CH2CF'3 131.0-13
1.5HCl13 CH2CF'3 153~
154I()l C12CF'20F379~81+
(C)I3 0H2CF'2CF'3 140~1
42HHCH20F'2Cr, ji 7111-like H
CH3CH2CF2CF'2H143,5-144.5
CH3)I CH2CF'2CF211 13'8
~139 Reference Example 3 2,3-dimethyl-4-(2,2,3,3-tetowo70
loproboxy)pyridine-1-oxide (2,69),
A number, 'san (113), was added to three sides of acetic anhydride (8πl), and after stirring at 110°C for 4 hours, ρ was prepared. Dissolve the distillate in 1v (2o) of methanol, add a solution of sodium hydroxide (1,2g) in water (5,000g), and stir at room temperature for 30 minutes.
Stir for a minute. t3 rice water was added and extracted with ethyl acetate μ. After drying with magnesium sulfate, the solvent was distilled off, applied to a column K of 7 likage/L/(50 g), dissolved in chloroform-methano/l' (10:1), and refiltered with isoderovir ether μ. When crystallized, 1.6 g of yellow crystals of 2-dioxymethoxy)v-3-methyA/-4-(2,2,3,3-tetoffluoropropoquine)pyridine were obtained, melting point 67-68°C above. In the same manner as above, the following compound (X7) was converted into compound (VI
) was manufactured.

〔ヒ　　会　　゛）勿　（■（） Ｒ２Ｒ３Ｒ４融点（℃） １１　　Ｅ　　ＣＨ２ＣＦ’３　　　　油、伏ＣＨ３Ｅ
　　　Ｃ）ｉ２０Ｆ’３　　　　　９３．５〜９４．Ｏ
ＨＩ　　ＣＵ２ＣＦ’２Ｃ７３油状 Ｃ１１３Ｕ　　ｃｌ（２ｃＦ’２ｃＦ’３　　　油状Ｈ
ＣＨ３Ｃ１１２ＣＦ’２０Ｆ３　　　　８７〜８９ＨＨ
Ｃ１１２ＣＦ’２ＣＦ’２Ｈ８８〜８９ＨＣＭ３Ｃｌｌ
２ＣＦ’２Ｃｒ２Ｈ９８〜　９９シ３考例４ ３．５−ジメチ／Ｌ’−４−ニトロピリジン−１−オキ
シド００９）、２．２．３．３．３−ペンタフロロプロ
パノ−Ｉしくｌ０ＩＦ）のｚ液に０℃でｔ−ブトキシカ
リウム（２ｇ）を１５分間かけて少しずつ加えたのち、
６０℃で１８時間かきまぜた。反応混合物にクロロｙｌ
ｑ　）レムを加え、セフイトろ過したのち、シリカゲル
（８０９）のカラムにｙ５ｓＬｒｆ　、ｆｆ１ｔｉｌｓ
’２エチμエステル−ヘキサン（１：１）、次いで２０
％メタノール−酎Ｑ（エチルエステル。[He meeting ゛) Mless (■ () R2R3R4 Melting point (℃) 11 E CH2CF'3 Oil, Fused CH3E
C) i20F'3 93.5-94. O
HI CU2CF'2C73 Oily C113U cl (2cF'2cF'3 Oily H
CH3C112CF'20F3 87~89HH
C112CF'2CF'2H88~89HCM3Cll
2CF'2Cr2H98-99C3 Example 4 3.5-dimethy/L'-4-nitropyridine-1-oxide 009), 2.2.3.3.3-pentafluoropropano-I-10IF) After adding potassium t-butoxy (2 g) little by little to solution Z at 0°C over 15 minutes,
Stir at 60°C for 18 hours. Chloroyl to the reaction mixture
q) After adding Rem and cephite filtration, y5sLrf and ff1tils were added to a silica gel (809) column.
'2ethyμ ester-hexane (1:1), then 20
% methanol-chuQ (ethyl ester).

で２出し、エーテル−ヘキサンから再結晶すると３．５
−ジメチ／ｌ／−４−（２，２，３，３，３−ペンタフ
ロロプロボキクンヒリジン−１−オキシドの結晶２．６
９が得られた。融点８９〜９１℃上記と同様にして化合
物（ＩＸ）から化合物（Ｘ）を製造した。When recrystallized from ether-hexane, 3.5 was obtained.
-dimethy/l/-4-(2,2,3,3,3-pentafluoroproboquicunehyridine-1-oxide crystal 2.6
9 was obtained. Compound (X) was produced from compound (IX) in the same manner as above.

化合物（Ｘ） Ｒ”　　　Ｒ３Ｒ’　　　　　　　ｈ“、！　点（℃ン
ＣＴｉ３ＨＣＨ２０Ｆ’３　　８２〜９４ＣＨ３ＣＨ３
ＣＨ２ＣＦ３　１３８〜１３９参考例５ ヨ、ラージメチｔｖ−４−Ｃｚ、ｚ、３．３．３−ペン
タフロロプロポキンクピリジン−１−オキシドＣ２，５
９）、ジメチ／ｌ／硫酸（１窮ｔ〕の混合物を１２０℃
で３０分間加熱したのち、メタノール（１２，５ｒ／）
１に加え、８０℃でｊａ　匝Ｑア７−ｕ　二７ム（４，
３ｇ）の水（２０イ）−メタノ−／ｌ／（ＬＯ＊１）ｒ
Ｂ液を３０分Ｏｉｌかけて滴下し、そのまま３０分１１
０かきまぜた。ＬＬＪ砧後氷を加え、炭ｎｉｌナトリウ
ムで中和したのち、クロロホルム抽出した。硫酸ナトリ
ウムでに・乞メ幕イ炎浴妨２を留去すると、３．５−ジ
メチ）ｖ−２−ヒドロキシメチ／’−４−（２，２，３
，３，３−ペンタフロロプロポキシ）ピリジンが油状物
としてｚ、ｚｑｍられた。Compound (X) R"R3R'h",! Point (°C CTi3HCH20F'3 82~94CH3CH3
CH2CF3 138-139 Reference Example 5 yo, largemethytv-4-Cz,z, 3.3.3-pentafluoropropoquine pyridine-1-oxide C2,5
9), dimethy/l/sulfuric acid (1 ton) mixture at 120°C.
After heating for 30 minutes, methanol (12.5r/)
In addition to 1, at 80℃
3g) of water (20i)-methanol-/l/(LO*1)r
Add liquid B dropwise for 30 minutes with oil, then leave it as it is for 30 minutes 11
0 stirred. After adding ice to the LLJ, the mixture was neutralized with sodium charcoal and extracted with chloroform. Distilling off the sodium sulfate solution gives 3,5-dimethy)v-2-hydroxymethy/'-4-(2,2,3
, 3,3-pentafluoropropoxy)pyridine as an oil.

上記と同様にして化合物（Ｘ）よシ化合物（■）を合成
した。Compound (X) and compound (■) were synthesized in the same manner as above.

）Ｉ　　　Ｃ）１３　　ＣＨ２ＣＦ３　　１１６〜１１
９実か；例１ ２−！）’ＧキＦメチ／レー３−／チ／１ｚ−４−（２
，２，３，３，３−ペンタフロロプロポキシ）ピリジン
（３５０２，７）の９ｏロホＡ／Ａ溶ｆｆ（１０＊ｌ）
に塩化チオニ／’　（０，２ｒｔｔ　）を加え、３０分
間加略還流したのち濃ωし、残留物をメタノ−／Ｌ／（
５欝／）にとかし、２−メμカプトベンツイミダゾール
（２００：ｘ／Ｉ）、２８％ナトリウムノトキシドン容
ａ（ｌｒり、メタノー／Ｉ／（６鱈ｔ）「；加え、３０
分間加熱通流した。メクノー／Ｌ／を留去し、水で加え
て酢酸エチルエステｐで抽出し、補水Ｑ化ナトリウム溶
液で洗滌後、硫酸マグネシウムで乾燥した。)I C)13 CH2CF3 116-11
9 fruit? Example 1 2-! )'G Ki F Mechi/Re 3-/Chi/1z-4-(2
,2,3,3,3-pentafluoropropoxy)pyridine (3502,7) in 9o RophoA/A solution ff (10*l)
Thioni chloride/' (0,2rtt) was added to the solution, refluxed for 30 minutes, concentrated, and the residue was dissolved in methanol/L/(
Add 2-mecaptobenzimidazole (200:
Heat current was applied for a minute. Mekno/L/ was distilled off, water was added, extracted with ethyl acetate P, washed with rehydrated sodium chloride solution, and dried over magnesium sulfate.

溶媒を留去後シリカゲ／Ｌ’（２０９）のカラムにかケ
、酢酸エチル−！−ステルーヘキサン（２：１）でｉ出
Ｌ、酢酸エチル−ヘキサンよシ再結晶すると、２−〔３
−メチ／Ｌ’−４−（２，２，３，３，３−ペンタフロ
ロプロポキシ）ビリジ−２−イル〕メチμチオベンツイ
ミダゾ−ｐ−死水和物の無色板状晶３７０ｔＩｇが得ら
れた。融点１４５〜１４６℃以下、上記と同様にして化
合物（］ＩＩと（ＩＮ）とを反応させ、目的化合物（Ｉ
　）　（ｎ−０）を製造した。After distilling off the solvent, it was poured into a Silicage/L' (209) column and ethyl acetate was added. 2-[3
-Methyl/L'-4-(2,2,3,3,3-pentafluoropropoxy)virid-2-yl]methyμthiobenzimidazo-p-dehydrated 370tIg of colorless plate crystals were obtained. . Compound (]II and (IN) are reacted in the same manner as above at a melting point of 145 to 146°C or lower to form the target compound (I).
) (n-0) was produced.

１１合物（Ｉ）　（ｎ−０） ＨＩＩ　　　ＨＣ１１２ＣＦ’３　　　　１３８〜１３
９−１１　　ＣＨ３１１Ｃ１２ＣＦ’３１４９〜１５０
ＨＨＣｎ３　　ＣＨ２ＣＦ’３　　　１６８〜１７０、
′″ ＨＣＨ３Ｃｌ１３ＣＨ２ＣＦ’３１５１．５〜１５ＺＯ
ＩＩ　　　　）Ｉ　　　ＨＣ）４２ＣＦ’２０Ｆ’３　
　１２５〜１２６Ｊ（）Ｉ　　　Ｃ１１３Ｃ１１２ＣＦ
２ＣＦ３　　１５１〜１５２ＦＩ　　Ｈ！Ｉ　　Ｃｎ２
ＣＦ’２ＣＦ２Ｆ！　　油状ＨＣＨ３ＩＩ　　　Ｃ：１
１２ＣＦ’２ＣＦ２Ｈｔ　３４〜１３５！（Ｔ（Ｃｌｌ
３　　Ｃｌｌ２ＣＰ’２Ｃ〜Ｈ１４８〜１４９ＩＩ　　
　ｃｎ３　　Ｃｌｌ３　　Ｃ１１２ＣＦ’２ＣＦ’３１
５８〜１６０・に３　５−ＣＦ３　　ＣＨ３Ｉｆ　　　
Ｃ１１２ＣＦ３　　　　　９２〜９３５−ＯＣＨ３ＣＴ
ｌ３　　　［４ＣＢ２ＣＦ３　　　　１５９〜１６０５
−ＯＣ１！３　　Ｔｌ　　　ＩＩ　　　Ｃｌ１２ＣＦ’
３　　　　１５２〜１５３丈施）５１１２ ２−　〔３−メ　チル−４−（２，２，３，３，３−ペ
ンタフロロプロポキシ）ヒ”リジー２−イル〕メチルナ
オベンツイミグゾール（２，２９）のクロロホルムＣ２
Ｏｎｌ）溶液に氷冷下ｍ−クロロ過安息香酸Ｃ１，３９
）のクロロ＊　／Ｌ／Ａ　（１５ｍｌ　）　Ｋ１１１ｔ
３０分かけて滴下したのち、反応液を旧イロ炭酸水素ナ
トリウム水溶液で洗滌した。硫酸マグネシウムで乾燥＠
濃縮し、シリカゲル（５０Ｆ）のカラムにかケ、酢酸エ
チルエステルで溶出し、アセトン−インプロピｙエーテ
ルより再醋ｄムすると、２−〔３−メチル−４−（２，
２，３，３，３−ベンタフＷＤプロポキク）ビリジ−２
−イ／ｌ／　）　−メチルス〃フィニルペンツイミダゾ
ールの倣黄色プリズム晶１．７ＢＱが得られたつｒコ点
１６１〜１６３℃（分解） 以下同様の方法で化合物（Ｉ）（ｎ−０）よシ化合物（
１）（ｎ−１）を製造した。11 Compound (I) (n-0) HII HC112CF'3 138-13
9-11 CH311C12CF'3149-150
HHCn3 CH2CF'3 168-170,
'''HCH3Cl13CH2CF'3151.5~15ZO
II ) I HC) 42CF'20F'3
125-126J()I C113C112CF
2CF3 151~152FI H! I Cn2
CF'2CF2F! Oily HCH3II C:1
12CF'2CF2Ht 34~135! (T(Cll
3 Cll2CP'2C~H148~149II
cn3 Cll3 C112CF'2CF'31
58～160・ni3 5-CF3 CH3If
C112CF3 92-935-OCH3CT
l3 [4CB2CF3 159-1605
-OC1!3 Tl II Cl12CF'
3 152-153 length) 5112 2-[3-Methyl-4-(2,2,3,3,3-pentafluoropropoxy)hy”lizy-2-yl]methylnaobenzimiguzole (2,29 ) of chloroform C2
Onl) Add m-chloroperbenzoic acid C1,39 to the solution under ice cooling.
) Chloro* /L/A (15ml) K111t
After adding dropwise over 30 minutes, the reaction solution was washed with an aqueous solution of sodium bicarbonate. Dry with magnesium sulfate
Concentrate, apply to a column of silica gel (50F), elute with ethyl acetate, and re-dilute with acetone-in-propyl ether to give 2-[3-methyl-4-(2,
2,3,3,3-Bentaf WD propokic) Viridi-2
-i/l/) -Imitation yellow prism crystals of methylsufinylpenzimidazole 1.7BQ were obtained at a point of 161-163°C (decomposition). compound (
1) (n-1) was produced.

ＩＩ　　　ｃｍ３　　ＨＣＴ（２ＣＦ３　　　１７８〜
１８２（ｄ））Ｉ　　　ＨＣＨ３Ｃ）１２０Ｆ３　　　
１７５〜１７７（ｄ）ＨＣｌｌ３　　Ｃｌ３　　ＣＨ２
ＣＦ’３　　　１７７〜１７８（ｄ）ＲＩＲ２ｉ１３Ｒ
’　　　　　ｌユ点（１）ＨＨｎ　　ｃｍ２ｃｒ２ｃｒ
３ｚ４８〜ｚｓｏ（ｄ）Ｔｌ　　　　’ＨＣ’Ｒ３ＣＩ
’１２０Ｆ’２０Ｆ’、５　　１４５〜１４８　（ｄ）
ＩＩ　　　　ＨＨａｎ２ｃｒ２ｃＦ２ｎ　　１３２〜１
３３！１　　　ＣＨ３ＩＩ　　ＣＨ２Ｃｒ２ＣＦ’２Ｂ
　　１４７〜１４８（ｄ）Ｈ！（ＣＨ３ＣＨ２ＣＦ’２
０Ｆ２Ｈ１３６〜１３９（ｄ）Ｅ　　　Ｃ１３ＣＨ３ｃ
ａ２ｃｙ２ｃｙ３　　１５７〜１５９５−ＣＦ３　　Ｃ
Ｈ３Ｉ　　Ｔ：Ｅ−−１６１〜Ｉ　Ｇ　２　（ｄ３５−
ＯＣＨ３ＣＨ３１ｒ　　　ＣＨ２ＣＦ’３　　　　　１
４０．５〜１４２　（ｄ）発明の効果 本発明の化合物（１）は、強め四階分泌押倒作用と胃粘
膜防模作用とを併有し、その結果顕著な抗潰瘍作用を示
し、ｔた比較的詩い物性的安定性を有し、マウスの急性
毒性試ｑ成績においても安全性が高い。従って本発明化
合物（１）は胃マａ瘍、士二指昂鷹扁、′ｖＪ炎などの
予防並びに治療に有用でちるやII cm3 HCT (2CF3 178~
182(d))I HCH3C)120F3
175-177(d) HCll3 Cl3 CH2
CF'3 177-178(d) RIR2i13R
' l yu point (1) HHn cm2cr2cr
3z48~zso(d)Tl 'HC'R3CI
'120F'20F', 5 145-148 (d)
II HHan2cr2cF2n 132-1
33!1 CH3II CH2Cr2CF'2B
147-148(d)H! (CH3CH2CF'2
0F2H136-139(d)E C13CH3c
a2cy2cy3 157-1595-CF3C
H3IT:E--161~I G2 (d35-
OCH3CH31r CH2CF'3 1
40.5-142 (d) Effects of the Invention The compound (1) of the present invention has both a strong effect of suppressing secretion and an effect of preventing gastric mucosa, and as a result shows a remarkable anti-ulcer effect, and It has relatively stable properties and is highly safe in acute toxicity tests on mice. Therefore, the compound (1) of the present invention is useful for the prevention and treatment of gastric ulcers, pharyngitis, 'vJ inflammation, etc.

Claims (2)

【特許請求の範囲】[Claims] （１）一般式 ▲数式、化学式、表等があります▼ 〔式中、Ｒ＾１は水素、メトキシまたはトリフルオロメ
チルを、Ｒ＾２およびＲ＾３は同一または異なって水素
またはメチルを、Ｒ＾４は炭素数２ないし５のフッ素化
された低級アルキルを、ｎは０または１をそれぞれ示す
。〕で表わされるピリジン誘導体またはその塩。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is hydrogen, methoxy or trifluoromethyl, R^2 and R^3 are the same or different and are hydrogen or methyl, R ^4 represents a fluorinated lower alkyl having 2 to 5 carbon atoms, and n represents 0 or 1, respectively. ] A pyridine derivative or a salt thereof. （２）一般式 ▲数式、化学式、表等があります▼ 〔式中、Ｒ＾１は水素、メトキシまたはトリフルオロメ
チルを示す。〕で表わされる化合物と一般式▲数式、化
学式、表等があります▼ 〔式中、Ｒ＾２およびＲ＾３は同一または異なって水素
またはメチルを、Ｒ＾４は炭素数２ないし５のフッ素化
された低級アルキルを、Ｘはハロゲン原子をそれぞれ示
す。〕で表わされる化合物とを反応させ、必要により酸
化反応に付すことを特徴とする一般式 ▲数式、化学式、表等があります▼ 〔式中、Ｒ＾１、Ｒ＾２、Ｒ＾３、Ｒ＾４およびｎは前
記と同意義を有する。〕で表わされるピリジン誘導体ま
たはその塩の製造法。(2) General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ [In the formula, R^1 represents hydrogen, methoxy or trifluoromethyl. ] Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc.▼ and X represents a halogen atom. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting with a compound represented by the following and subjecting it to an oxidation reaction if necessary ▼ [In the formula, R^1, R^2, R^3, R ^4 and n have the same meanings as above. ] A method for producing a pyridine derivative or a salt thereof.
JP59171069A 1984-08-16 1984-08-16 Pyridine derivative and preparation thereof Granted JPS6150978A (en)

Priority Applications (32)

Application Number Priority Date Filing Date Title
JP59171069A JPS6150978A (en) 1984-08-16 1984-08-16 Pyridine derivative and preparation thereof
US06/760,568 US4628098A (en) 1984-08-16 1985-07-29 2-[2-pyridylmethylthio-(sulfinyl)]benzimidazoles
DE8585305458T DE3569736D1 (en) 1984-08-16 1985-07-31 Pyridine derivatives and their production
EP19850305458 EP0174726B1 (en) 1984-08-16 1985-07-31 Pyridine derivatives and their production
DE19975020C DE19975020I2 (en) 1984-08-16 1985-07-31 Pyridine derivatives and their preparation.
AT85305458T ATE42554T1 (en) 1984-08-16 1985-07-31 PYRIDINE DERIVATIVES AND THEIR PRODUCTION.
DE19975017C DE19975017I2 (en) 1984-08-16 1985-07-31 Pyridine derivatives and their preparation.
DK356485A DK171340B1 (en) 1984-08-16 1985-08-06 Substituted 2 - ((4-fluoroalkoxypyrid-2-yl) methylthio or methylsulfinyl) benzimidazoles, process for their preparation and pharmaceutical composition containing such a compound
AU45895/85A AU570130B2 (en) 1984-08-16 1985-08-07 2-pyridylmethylthio-and 2-pyridylmethylsulfinyl benzimidazole derivatives
IE197685A IE58363B1 (en) 1984-08-16 1985-08-09 Pyridine derivatives and their production
PH32628A PH20946A (en) 1984-08-16 1985-08-13 Pyridine derivatives and their production
GR851981A GR851981B (en) 1984-08-16 1985-08-13
ZA856117A ZA856117B (en) 1984-08-16 1985-08-13 Pyridine derivatives and their production
SU3947161A SU1507211A3 (en) 1984-08-16 1985-08-14 Method of producing pyridine derivatives
CA000488662A CA1255314A (en) 1984-08-16 1985-08-14 2-(pyrid-2-yl)-methylthio(or methylsulfinyl) benzimidazole derivatives and their production
KR1019850005863A KR920002128B1 (en) 1984-08-16 1985-08-14 Process for preparing pyridine derivatives
UA3947161A UA7140A1 (en) 1984-08-16 1985-08-14 Method for producing pyridine derivatives
ES546152A ES8607288A1 (en) 1984-08-16 1985-08-14 Pyridine derivatives and their production.
NO853226A NO163131C (en) 1984-08-16 1985-08-15 Analogous Process for Preparation of Therapeutically Active Pyridine Derivatives.
HU853151A HU195210B (en) 1984-08-16 1985-08-15 Process for producing pyridine derivatives and pharmaceutical preparations comprising these compounds as active substance
US06/937,193 US4689333A (en) 1984-08-16 1986-12-02 2-(2-pyridylmethylthio (sulfinyl)) benzimidazoles
MYPI87002685A MY102116A (en) 1984-08-16 1987-09-30 Pyridine derivatives and their production
SG1032/91A SG103291G (en) 1984-08-16 1991-12-04 Pyridine derivatives and their production
HK47/92A HK4792A (en) 1984-08-16 1992-01-16 Pyridine derivatives and their production
MX9203043A MX9203043A (en) 1984-08-16 1992-06-19 PIRIDINE DERIVATIVES.
LV920583A LV5091A3 (en) 1984-08-16 1992-12-30 Method of obtaining pyridine derivatives
GEAP1993601A GEP19960313B (en) 1984-08-16 1993-03-11 Method for Production of Pyridin Derivatives
LTRP440A LT2118B (en) 1984-08-16 1993-03-19 PIRIDINE'S WAY OF RECEIVING
NL930109C NL930109I2 (en) 1984-08-16 1993-06-29 Pyridine derivatives and their preparation.
BG98459A BG60415B2 (en) 1984-08-16 1994-02-11 Pyridine derivatives and their preparation
NO1995002C NO1995002I1 (en) 1984-08-16 1995-03-31 Lansoprazole / 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -pyrid-2-yl] methylsylfinylbenzimidazole
LV960208A LV5775B4 (en) 1984-08-16 1996-07-02 Pyridine derivatives and their yield

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP59171069A JPS6150978A (en) 1984-08-16 1984-08-16 Pyridine derivative and preparation thereof

Publications (2)

Publication Number Publication Date
JPS6150978A true JPS6150978A (en) 1986-03-13
JPH0244473B2 JPH0244473B2 (en) 1990-10-04

Family

ID=15916456

Family Applications (1)

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JP59171069A Granted JPS6150978A (en) 1984-08-16 1984-08-16 Pyridine derivative and preparation thereof

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US (2) US4628098A (en)
EP (1) EP0174726B1 (en)
JP (1) JPS6150978A (en)
KR (1) KR920002128B1 (en)
AU (1) AU570130B2 (en)
BG (1) BG60415B2 (en)
CA (1) CA1255314A (en)
DE (3) DE19975017I2 (en)
DK (1) DK171340B1 (en)
ES (1) ES8607288A1 (en)
GE (1) GEP19960313B (en)
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NO853226L (en) 1986-02-17
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AU570130B2 (en) 1988-03-03
US4628098A (en) 1986-12-09
PH20946A (en) 1987-06-10
DE3569736D1 (en) 1989-06-01
CA1255314A (en) 1989-06-06
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MX9203043A (en) 1992-07-01
NL930109I1 (en) 1993-10-18
ES8607288A1 (en) 1986-05-16
HUT39444A (en) 1986-09-29
ZA856117B (en) 1986-04-30
BG60415B2 (en) 1995-02-28
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GEP19960313B (en) 1996-06-24
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HU195210B (en) 1988-04-28
UA7140A1 (en) 1995-06-30
SG103291G (en) 1993-02-19
NL930109I2 (en) 1997-02-03
EP0174726B1 (en) 1989-04-26
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US4689333A (en) 1987-08-25
NO1995002I1 (en) 1995-03-31
ES546152A0 (en) 1986-05-16
HK4792A (en) 1992-01-17
NO163131C (en) 1994-10-24
EP0174726A1 (en) 1986-03-19

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